This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The blood-retinal barrier (BRB) selectively and tightly regulates the local environment of the neural retina. Loss of BRB integrity is a common pathology in three major causes of blindness: diabetic retinopathy;age-related macular degeneration;and retinopathy of prematurity. Recent evidence indicates that caveolin-1 (Cav-1) is essential for normal retinal function and BRB integrity. Cav-1 null mice display reduced retinal function by electroretinography that cannot be explained by loss of Cav-1 specifically in photoreceptors. Thus, the functional deficit in Cav-1 null retinas likely results from an abnormal local environment surrounding photoreceptors. In support of this hypothesis, compelling evidence indicates that Cav-1 null mice display a clear loss of RPE and vascular barrier functions that correlate with alterations in tight junctions, changes in Na/K-ATPase activity, and outer retinal edema. The goals of this COBRE project are to examine the mechanism(s) by which Cav-1 regulates BRB integrity in the RPE. These goals are aligned with an R01 application submitted in March 2009. The first aim of the R01 application is designed to determine the role of Cav-1 in regulating barrier activity specifically within the RPE using cell-specific, inducible genetic deletion. The second aim will test the role of Cav-1 in the structural organization of lipids and proteins in epithelial cell-cell contacts and apical process. The final aim will focus on the role that dysregulation of the Na/K-ATPase plays and how Cav-1 regulates ATPase activity.